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How malaria parasites reproduce: new insights
How malaria parasites reproduce: new insights
About the study
- Malaria is a major health concern worldwide, resulting in approximately 429,000 deaths in 2015 (World Health Organisation, 2016)
- Malaria parasites are transmitted between mammalian hosts by mosquitoes. Their transmission to the mosquito vector is an important, but unclear part of the process
- EMBL-EBI researchers have broken down the little-known molecular systems that regulate parasite development during transmission to mosquitoes.
A study led by researchers at the European Bioinformatics Institute (EMBL-EBI) and the Wellcome Trust Sanger Institute gives new insights into the life cycle of malaria-causing Plasmodium parasites, as they are transmitted from mammal to mosquito. Using mass spectrometry and computational biology, the collaborators explored what happens during this rapid process, which spurs the spread of the deadly disease.
How it works
During one stage of their life-cycle, malaria parasites have male and female ‘gametocyte’ forms, which play an important role in Plasmodium reproduction. These gametocytes linger in the blood of mammals, waiting to be ingested by mosquitoes. As soon as they get into the mosquito, they swing into action.
Within ten minutes, the male gametocytes undergo several extreme changes: they reproduce their genome three times and go through three rounds of endomitosis (when newly copied chromosomes are separated within the cell nucleus). This produces ‘microgametes’: sperm-like structures that make their way to female gametocytes and reproduce. The cells produced in this process can leave the mosquito’s body to infect another host – for example, a person.
Researchers have observed this process for years, yet they know very little about how it works at a molecular level.
What did the researchers do?
This latest study tracks gametocytes from the moment they are ingested by a mosquito. The authors looked specifically at the protein signalling involved in controlling that crucial first minute in the mosquito’s body, when the gametocyte is activated.
To get a clear picture of what is happening, the team used mass spectrometry to investigate protein phosphorylation – a measure of proteins being activated, deactivated or modified. Protein phosphorylation is a good indicator of what is happening in a cell at any given time.
The researchers focused primarily on the first 18 seconds of the process. They took a ‘snapshot’ of phosphorylation levels every six seconds, which allowed them to identify which proteins undergo changes during that critical first stage of reproduction.
The breadth of activity was unlike anything they expected to see.
“We found hundreds of proteins that are phosphoregulated simultaneously within the first 18 seconds of gametocyte activation. This insight could help us understand protein activation. That would point us to which proteins play an active part in the transmission of the parasite at this stage,” explains Brandon Invergo, lead author and ESPOD postdoctoral fellow at EMBL-EBI and The Sanger Institute.
What did they find?
Understandably, the majority of the proteins being regulated when reproduction kicks off are related to the cell cycle. What the researchers found most interesting was the near-simultaneous regulation of proteins that are related to different steps in the cell cycle.
Typically, the cell cycle is considered to be a rigid series of steps that happen one after the other – not all at the same time. The findings suggest a potentially different mode of regulation within the malaria parasite. While there have been hints of unusual cell cycle behaviour in malaria parasites, this is the most direct evidence yet that these species do things differently.
“We know very little about the malaria parasite, especially when it comes to the function of its different proteins,” continued Invergo. “Our study suggests that processes in the cell cycle are occurring simultaneously, which contradicts our usual understanding of cell cycle biology. Also, the speed with which the process happens is extremely interesting. We expected it to be fast, but not quite this fast.”
Why does it matter?
“If we want to have any hope of reducing malaria infection rates and improving treatments, we need to understand how the parasite works. This type of research helps us break down what is happening in the parasite, step by step, at a molecular level. It could also help us identify proteins that, if targeted, could stop the transmission of the parasite, and thus block the malaria from infecting a new host,” says Pedro Beltrao, Group Leader at EMBL-EBI.
This study focuses on the fundamental biology driving malaria, so while it may not directly lead to the eradication of the parasite, it offers new insights that can direct future research in promising directions.
This research wouldn’t have been possible without the collaboration between EMBL-EBI and the Wellcome Trust Sanger Institute’s Proteomics Mass Spectrometry lab and Malaria Programme. Brandon Invergo is an EBI–Sanger postdoctoral (ESPOD) fellow. The ESPOD programme focuses on projects that combine experimental (wet-lab) and computational (dry-lab) approaches.
INVERGO, B.M., et al. (2017). Sub-minute Phosphoregulation of Cell Cycle Systems during Plasmodium Gamete Formation.Cell Reports Vol 21, issue 7, pages 2017-2029. Published online 14/11; DOI:10.1016/j.celrep.2017.10.071